Selected 2017 Publications

Author Correction: A System of Cytokines Encapsulated in ExtraCellular Vesicles.

Fitzgerald W, Freeman ML, Lederman MM, Vasilieva E, Romero R, Margolis L.

Sci Rep 2020 Oct;10(1):18935. doi: 10.1038/s41598-020-75735-w. Epub.

Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper. © Scientific Reports.

In vitro exposure of leukocytes to HIV pre-exposure prophylaxis (PrEP) decreases mitochondrial function and alters gene expression profiles.

Bowman ER, Cameron C, Richardson B, Kulkarni M, Gabriel J, Kettelhut A, Hornsby L, Kwiek JJ, Turner AN, Malvestutto C, Bazan J, Koletar SL, Doblecki-Lewis S, Lederman MM, Cameron M, Klatt NR, Lake JE, Funderburg NT.

Antimicrob Agents Chemother 2020 Oct;():. doi: 10.1128/AAC.01755-20. Epub.

Abstract: : The use of antiretroviral therapy (ART) as pre-exposure prophylaxis (PrEP) is an effective strategy for preventing HIV acquisition. The cellular consequences of PrEP exposure, however, have not been sufficiently explored to determine potential effects on health in individuals without HIV.: Peripheral blood mononuclear cells (PBMCs) from people without HIV were exposed to tenofovir disoproxil fumarate (TDF) or emtricitabine (FTC) overnight. Mitochondrial mass and function were measured by flow cytometry and Agilent XFp analyzer. Monocyte-derived macrophages (MDMs) were differentiated in 20% autologous serum for 5 days in the presence or absence of TDF or FTC, and surface markers, lipid uptake, and efferocytosis were measured by flow cytometry. MDM gene expression was measured using RNAseq. Plasma lipids were measured using mass spectrometry.: PBMCs exposed to TDF or FTC had decreased maximal oxygen consumption rate (OCR) and reduced mitochondrial mass. Exposure to PrEP also increased reactive oxygen species (ROS) production from monocyte subsets. Compared to MDMs cultured in medium alone, cells differentiated in the presence of TDF (829 genes) or FTC (888) genes had significant changes in gene expression. Further, PrEP-exposed MDMs had decreased mitochondrial mass, and displayed increased lipid uptake and reduced efferocytosis. Plasma biomarkers and lipid levels were also altered in individuals receiving a PrEP regimen.: Exposure of leukocytes to TDF or FTC resulted in decreased mitochondrial function, and altered functional and transcriptional profiles. These findings may have important implications for the metabolic and immunologic consequences of PrEP in populations at risk for HIV acquisition. © Antimicrobial Agents And Chemotherapy.

Macrophage maturation from blood monocytes is altered in people with HIV, and is linked to serum lipid profiles and activation indices: A model for studying atherogenic mechanisms.

Bowman ER, Cameron CM, Richardson B, Kulkarni M, Gabriel J, Cichon MJ, Riedl KM, Mustafa Y, Cartwright M, Snyder B, Raman SV, Zidar DA, Koletar SL, Playford MP, Mehta NN, Sieg SF, Freeman ML, Lederman MM, Cameron MJ, Funderburg NT.

PLoS Pathog 2020 Oct;16(10):e1008869. doi: PPATHOGENS-D-20-01053. Epub.

Abstract: People with HIV (PWH) are at increased risk for atherosclerotic cardiovascular disease (ASCVD). Proportions of vascular homing monocytes are enriched in PWH; however, little is known regarding monocyte-derived macrophages (MDMs) that may drive atherosclerosis in this population. We isolated PBMCs from people with and without HIV, and cultured these cells for 5 days in medium containing autologous serum to generate MDMs. Differential gene expression (DGE) analysis of MDMs from PWH identified broad alterations in innate immune signaling (IL-1β, TLR expression, PPAR βδ) and lipid processing (LXR/RXR, ACPP, SREBP1). Transcriptional changes aligned with the functional capabilities of these cells. Expression of activation markers and innate immune receptors (CD163, TLR4, and CD300e) was altered on MDMs from PWH, and these cells produced more TNFα, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs) than did cells from people without HIV. MDMs from PWH also had greater lipid accumulation and uptake of oxidized LDL. PWH had increased serum levels of free fatty acids (FFAs) and ceramides, with enrichment of saturated FAs and a reduction in polyunsaturated FAs. Levels of lipid classes and species that are associated with CVD correlated with unique DGE signatures and altered metabolic pathway activation in MDMs from PWH. Here, we show that MDMs from PWH display a pro-atherogenic phenotype; they readily form foam cells, have altered transcriptional profiles, and produce mediators that likely contribute to accelerated ASCVD. © PLoS Pathogens.

CX3CL1 and IL-15 Promote CD8 T cell chemoattraction in HIV and in atherosclerosis.

Panigrahi S, Chen B, Fang M, Potashnikova D, Komissarov AA, Lebedeva A, Michaelson GM, Wyrick JM, Morris SR, Sieg SF, Paiardini M, Villinger FJ, Harth K, Kashyap VS, Cameron MJ, Cameron CM, Vasilieva E, Margolis L, Younes SA, Funderburg NT, Zidar DA, Lederman MM, Freeman ML.

PLoS Pathog 2020 09;16(9):e1008885. doi: PPATHOGENS-D-20-00809. Epub.

Abstract: Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded. © PLoS Pathogens.

Pathogenesis of Aging and Age-related Comorbidities in People with HIV: Highlights from the HIV ACTION Workshop.

Gabuzda D, Jamieson BD, Collman RG, Lederman MM, Burdo TH, Deeks SG, Dittmer DP, Fox HS, Funderburg NT, Pahwa SG, Pandrea I, Wilson CC, Hunt PW.

Pathog Immun 2020 ;5(1):143-174. doi: pai.v5i1.365. Epub.

Abstract: People with HIV (PWH) experience accentuated biological aging, as defined by markers of inflammation, immune dysfunction, and the epigenetic clock. They also have an elevated risk of multiple age-associated comorbidities. To discuss current knowledge, research gaps, and priorities in aging and age-related comorbidities in treated HIV infection, the NIH program staff organized a workshop held in Bethesda, Maryland in September 2019. This review article describes highlights of discussions led by the Pathogenesis/Basic Science Research working group that focused on three high priority topics: immunopathogenesis; the microbiome/virome; and aging and senescence. We summarize knowledge in these fields and describe key questions for research on the pathogenesis of aging and age-related comorbidities in PWH. Understanding the drivers and mechanisms underlying accentuated biological aging is a high priority that will help identify potential therapeutic targets to improve healthspan in older PWH. © Pathogens & Immunity.

SARS-CoV-2 and ACE2: The biology and clinical data settling the ARB and ACEI controversy.

Chung MK, Karnik S, Saef J, Bergmann C, Barnard J, Lederman MM, Tilton J, Cheng F, Harding CV, Young JB, Mehta N, Cameron SJ, McCrae KR, Schmaier AH, Smith JD, Kalra A, Gebreselassie SK, Thomas G, Hawkins ES, Svensson LG.

EBioMedicine 2020 Aug;58():102907. doi: 10.1016/j.ebiom.2020.102907. Epub.

Abstract: SARS-CoV-2 enters cells by binding of its spike protein to angiotensin-converting enzyme 2 (ACE2). Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have been reported to increase ACE2 expression in animal models, and worse outcomes are reported in patients with co-morbidities commonly treated with these agents, leading to controversy during the COVID-19 pandemic over whether these drugs might be helpful or harmful. © EBioMedicine.

Massive release of CD9+ microvesicles in HIV infection, regardless of virologic control.

Poveda E, Tabernilla A, Fitzgerald W, Salgado-Barreira Á, Grandal M, Pérez A, Mariño A, Álvarez H, Valcarce N, González-García J, Bernardino JI, Gutierrez F, Fujioka H, Crespo M, Ruiz-Mateos E, Margolis L, Lederman MM, Freeman ML, .

J Infect Dis 2020 Jun;():. doi: 10.1093/infdis/jiaa375. Epub.

Abstract: The role of extracellular vesicles (EVs) in HIV pathogenesis is unknown. We examine the cellular origin of plasma microvesicles (MVs), a type of ectocytosis-derived EV, the presence of mitochondria in MVs, and their relationship to circulating cell-free mitochondrial DNA (ccf-mtDNA) in HIV-infected patients and controls. © The Journal Of Infectious Diseases.

Antiretroviral Treatment for HIV Elite Controllers?

Ruiz-Mateos E, Poveda E, Lederman MM.

Pathog Immun 2020 ;5(1):121-133. doi: pai.v5i1.364. Epub.

Abstract: In most HIV-infected persons, the natural history of untreated infection is one of sustained viremia, progressive CD4 T cell depletion with resultant morbidity and mortality. The advent of effective combination antiretroviral therapy (ART) that controls HIV replication has altered this landscape dramatically. Yet a rare population of HIV-infected persons-elite controllers (EC)-can control HIV replication such that plasma levels of virus are "undetectable" without ART. The EC phenotype is heterogeneous, with some subjects durably controlling the virus-persistent elite controllers-and some eventually losing viral control-transient elite controllers. Overall, EC tend to have robust HIV-specific T cell responses and in some cases, mainly in transient elite controllers, elevated activation and inflammation indices that diminish with ART suggesting that endogenous defenses against this persistent pathogen come at the cost of heightened activation/inflammation. A limited data set suggests that cardiovascular disease risk as well as the occur-rence of other morbid events may be greater in the overall EC population than in treated HIV infection. ART in EC decreases activation indices but does not appear to increase circulating CD4 T cell numbers nor do we know if it alters clinical outcomes. Thus, it is difficult to recommend or discourage a decision to start ART in the EC population but the authors lean toward treatment particularly in those EC whose activation indices are high and those who are progressively losing circulating CD4 T cell numbers. Biomarkers that can reliably predict loss of virologic control and immune failure are needed. © Pathogens & Immunity.

'Rinse and Replace': Boosting T Cell Turnover To Reduce HIV-1 Reservoirs.

Grossman Z, Singh NJ, Simonetti FR, Lederman MM, Douek DC, Deeks SG, .

Trends Immunol 2020 06;41(6):466-480. doi: 10.1016/ Epub.

Abstract: Latent HIV-1 persists indefinitely during antiretroviral therapy (ART) as an integrated silent genome in long-lived memory CD4 T cells. In untreated infections, immune activation increases the turnover of intrinsically long-lived provirus-containing CD4 T cells. Those are 'washed out' as a result of their activation, which when coupled to viral protein expression can facilitate local inflammation and recruitment of uninfected cells to activation sites, causing latently infected cells to compete for survival. De novo infection can counter this washout. During ART, inflammation and CD4 T cell activation wane, resulting in reduced cell turnover and a persistent reservoir. We propose accelerating reservoir washout during ART by triggering sequential waves of polyclonal CD4 T cell activation while simultaneously enhancing virus protein expression. Reservoir reduction as an adjunct to other therapies might achieve lifelong viral control. © Trends In Immunology.

Inflammescent CX3CR1+CD57+CD8+ T cells are generated and expanded by IL-15.

Morris SR, Chen B, Mudd JC, Panigrahi S, Shive CL, Sieg SF, Cameron CM, Zidar DA, Funderburg NT, Younes SA, Rodriguez B, Gianella S, Lederman MM, Freeman ML.

JCI Insight 2020 06;5(11):. doi: 10.1172/jci.insight.132963. Epub.

Abstract: HIV infection is associated with an increase in the proportion of activated CD8+ memory T cells (Tmem) that express CX3CR1, but how these cells are generated and maintained in vivo is unclear. We demonstrate that increased CX3CR1 expression on CD8+ Tmem in people living with HIV (PLWH) is dependent on coinfection with human CMV, and CX3CR1+CD8+ Tmem are enriched for a putatively immunosenescent CD57+CD28- phenotype. The cytokine IL-15 promotes the phenotype, survival, and proliferation of CX3CR1+CD57+CD8+ Tmem in vitro, whereas T cell receptor stimulation leads to their death. IL-15-driven survival is dependent on STAT5 and Bcl-2 activity, and IL-15-induced proliferation requires STAT5 and mTORC1. Thus, we identify mechanistic pathways that could explain how "inflammescent" CX3CR1+CD57+ CD8+ Tmem dominate the overall memory T cell pool in CMV-seropositive PLWH and that support reevaluation of immune senescence as a nonproliferative dead end. © JCI Insight.